AML: Treatment Advances

Participants:     Dr. Alice Mims, The Ohio State University

Lindsey Whyte, Leukemia Research Foundation

- Hello everyone. Thanks so much for joining us for the third installment of this year's New & Emerging Treatment series. The topic of this session is AML and we're joined by Dr. Alice Mims of The Ohio State University, who will share some slides about the latest treatments and research for AML and respond to questions from participants. My name is Lindsey Whyte and I am the Director of Programs & Partnerships at the Leukemia Research Foundation.

- I'd just like to take a moment to recognize the supporters of this event, this series- AstraZeneca, Autolus, Kite, Merck and Pfizer.

- The Leukemia Research Foundation's mission is to cure leukemia through innovative research funding and to support patients and families. The Foundation has raised over $90 million in support of its mission since our founding in 1946 and has funded research grants to over 750 investigators worldwide. Our support programs for leukemia patients and their loved ones include information and resources, education programs, financial assistance, and a directory of other helpful organizations and resources on our website.

- For today's program, all participants will be muted throughout, but we welcome your questions in the Q&A box at the bottom of the screen, the zoom screen. Please note that if you want for your question to be anonymous, you have to check the button to make sure that your name is not shown. So there is a little box there that you checked so your name isn't shown with your question. If you already submitted a question through the registration, please know that we have the questions and we'll do our best to cover as many as possible. After today's program, you'll be sent a brief evaluation through email. Please take a moment to complete the evaluation so that we can improve our future programs. Also, this program will be recorded and we will send a link to the recording to all registrants after, you know, in a week or so, once we've had a chance to go through the video.

- We are grateful to have Dr. Alice Mims with us today. Dr. Mims is a professor at The Ohio State University and she specializes in treating patients with acute and chronic myeloid diseases, in particular acute myeloid leukemia. She is an NCI funded clinical researcher who focuses on the development of novel therapeutics/clinical trials to help improve treatment options and outcomes for patients with these diagnoses. Within the OSU Comprehensive Cancer Center, Dr. Mims serves as co-leader for the Leukemia and Hematological Malignancies program, where she oversees collaborative research initiatives for translational projects and provides mentorship of clinical scholars. Dr. Mims also serves as Senior Medical Director of the Leukemia & Lymphoma Society's multi-institutional umbrella study Beat AML that assesses new target therapeutics in older patients with the hope to move away from chemotherapy and towards more individualized targeted treatments. Dr. Mims, thank you so much for joining us today. Please, let's get things started with an overview of the latest treatments, research and trials for AML.

- Okay, I can't share my screen.

- Sorry about that.

- But hi everyone, I'm so happy to be here today and talk with you all about just all the exciting research that's going on for patients with acute myeloid leukemia and answer, you know, whatever questions you may have that may, you know, help you on your journey as well.

- Let's see. And you all can see that okay?

- Yes.

- Okay. So what I would like to try to take the time to go over in this webinar is just do a brief overview of acute myeloid leukemia just to help with some maybe understanding of some of the next topics with targeted therapeutics going over different inhibitors that have been more recently approved acute myeloid leukemia, including FLT3 inhibitors, IDH inhibitors and then more recently menin inhibitors. And briefly discuss other potential targeted therapies that are being looked at in clinical trials. And then also the topic of cellular and immunotherapy and some different, you know, studies that are along the way with antibody therapies, CAR T cell and natural killer cellular therapy. And then briefly talk about a subtype of acute myeloid leukemia, acute promyelocytic leukemia.

- So I wanted to just briefly start off by showing the slide of normal hematopoiesis. And so that means just how the bone marrow makes normal blood cells and kind of show what's going awry when acute myeloid leukemia develops. And essentially over here on the left you can see that these are where your stem cells and then your common myeloid progenitor, a factory that makes different types of myeloid cells, has abnormal signaling and really starts over developing these myeloblasts which are abnormal and not normal cells that go on to make healthy white blood cells. And so that really impacts your ability in your bone marrow to produce red blood cells which come from erythrocytes, platelets which come from megakaryocytes, and then other good infection fighting cells, especially neutrophils, which many of you may know when those are low, you're at more risk for bacterial infections. So essentially this is what we've seen in the bone marrow biopsy if we take a sample, is it's just filled with these abnormal myeloblasts and why patients present with, you know, low counts or maybe sometimes high white blood cell counts that are typically just made of these blast cells.

- So traditionally acute myeloid leukemia was diagnosed when people had 20% blast myeloblast or greater in the bone marrow or blood. However, there are new classifications that have come out in the past few years that with the WHO and something called the ICC, that that's somewhat changing. And so there can be genetic abnormalities. There's certain things that we call core binding factor AML translocations in with 8;21 or inversion 16 that define AML regardless of blast percentage. And then also we can have where we call this MDS or myelodysplastic syndrome, AML kind of overlap where patients can have certain mutations and can have at least 10% of blasts or higher and can act similar to AML with 20% blasts or higher. And so it's important as you're talking with your, you know, hematologist or oncologist about your diagnosis, just to understand what are these different features of your acute myeloid leukemia because it can impact the diagnosis, it can impact chance of cure, prognosis, also your therapeutic options and then also clinical trial options beyond just traditional FDA approved treatments.

- When we talk to patients about kind of outcomes for acute myeloid leukemia, it's different than what you think about with solid tumors such as breast cancer, lung cancer, that we don't stage it, you know, from stage one to stage four. We more look at, as I mentioned, chromosome abnormalities, mutations that are in these abnormal leukemia cells that help us predict how patients may do and think about therapies to give best chance for cure. And so traditionally for a long time, we've looked at this risk category over to the left and talked about favorable subtypes which may be cured with chemotherapy by itself, intermediate where we may think about chemotherapy by itself or may think about transplant for best chance of cure. And then adverse risk which we would definitely recommend transplant for patients if they get into remission as well as we know that's likely the only chance of cure.

- However, what really has been learned is most of this data was based off of patients who received intensive chemotherapy and we're applying it to all comers older patients, people who weren't able to receive intensive chemotherapy and still talking about prognosis. And so more recently the ELN, which is a European Leukemia Net, which is a group of experts, came together to look at different features for patients who see non-intensive chemotherapies for the mainstay of Venetoclax- Azacitidine-based treatment and to think about outcomes. And those, although those therapies are not traditionally considered curative, we can have some patients who may be cured, in particular potentially NPM1 patients with NPM1 mutations or patients who can just have long, longer survival, longer responses to treatment which is considered favorable while those with intermediate may respond to treatment, but that is traditionally a little bit shorter. And then this adverse risk, which is mutated TP53 who traditionally have less of, much less of a chance to respond of any traditional less intensive chemotherapy or less intensive chemotherapy. And we really have to think about clinical trials for patients with these types of mutations to try to figure out better chance of cure and response.

- And then one thing I also wanted to briefly mention because this is going to come up during the talk, are different levels of response for patients. And so when we talk about responses, these are not responses that define cure, but these are levels of remission. We want to see disease control to try to see if we can move forward towards cure, move forward towards allogeneic transplant. And the deeper the level of remission, the more likely that patients can have curative intent if they are candidates for more intensive treatment or able to go on to allogeneic transplantation. So complete remission is kind of what we aim for, where we want to have bone marrow blasts less than 5% and then also have full recovery of neutrophil count greater than a thousand, platelet count greater than a hundred thousand. And some of these, as you can see defined below complete remission with partial hematologic recovery, you may have the bone marrow blasts less than 5%, but don't quite need those levels of ANC or platelet count that are still clinically meaningful because typically risk of infection is, is better when you have a higher at absolute neutrophil count. And then also not needing transfusions with platelets when platelet goal is over 50,000. And MLFS is morphological leukemia free state. And so that's where we don't see leukemia cells but counts have not recovered. And when we see that, we want to typically give patients time to see if they'll fully recover or we worry there's still persistent disease.

- Now some of the slides that I'll talk about, we'll discuss overall response rate and that's really just combining all these levels of remission along with that morphological leukemia free state and studies. And then composite complete remission rate includes all of those levels of remission, but does not include morphological leukemia free state. So since before 2017, really what our options were for patients for treatment were intensive chemotherapy, traditionally what we call seven plus three induction, which is daunorubicin was cytarabine chemotherapies combined and then consolidated chemotherapy. Or for patients who weren't candidates, we give hypomethylating agents like Azacitidine or Decitabine, a single agent for more palliative intent. And so since 2017 we've had 12 new drug approvals in AML, which is wonderful because we're seeing improved remission rates, longer survival, and more patients being cured of their disease.

- And so we will go through some of these different therapies on the upcoming slides, but what I will say is one of the most impactful treatments to date has been this Venetoclax, which is a BCL2 inhibitor and adding that to hypomethylating agents has shown for patients who are not intensive induction candidates really improved complete remission rates up to 75-80%. And overall survival is also greatly improved instead of using hypomethylating agents by themselves.

- So when we see patients, when we see new patients, patients who have this diagnosis, things that we really want to think about when thinking about therapeutic approaches and talking with patients and their families are some of these things that follow. So doing our best job to see about performance status, which means how much are people getting up out of bed? How, how much are they able to do activities of daily living? Do we think they could tolerate intensive chemotherapy? Do we think less intensive chemotherapy may be a better route to go? Of course the most important thing is thinking about patient preference and goals.

- So it's really important that your physician talks to you and understands what your goals are with these diagnosis as you're learning more about it and thinking it through with your family. Sometimes we need to think about starting treatment right away because patients can present with a really high white blood cell count that can be dangerous because it can cause something called leukostasis where there's the blast cells can clog up capillaries, so small blood vessels and can lead to strokes, heart attacks, patients can present with abnormal clotting factors where they're at higher risk for bleeding. And so sometimes we can't wait on all the pieces of the puzzle such as chromosomes or changes or cytogenetics or mutational status because we worry that patients won't be able to make it if we don't start treatment right away. Fortunately that is not the majority of most patients these days.

- We also want to think about what are the side effects of treatments, how does that affect individual patients based off of other diagnoses they may have, other medications they may need to take and what may be the safer option if we have choices? Are patients going to have potential curative approaches? Do we think they may be a transplant candidate? And what are our best ways to get to these curative approaches? Again, co-mutational status, looking at different mutations that may be in the leukemia cell cytogenetics, and I just put this little reminder here to myself that if disease comes back, if there's relapse, it's really important to recheck those because those can change. So mutations can go away, new ones can occur. And so you want to be most up to date with what your options are.

- MRD is measurable residual disease assessments. And so that's looking at are there still low levels of disease such as mutations still being positive. Flow cytometry, which is a specific test looking for abnormal markers on blast cells and those may affect next steps after you achieve your initial remission for further treatment or maintenance therapies in certain situations. And then clinical trial availability. And then also unfortunately, insurance and prior authorizations may impact as sometimes that can take a while to get approvals for certain medications. And so sometimes we have to, or they can be prohibitively expensive and that may impact our choices. But fortunately that's not the case for most patients because there are great grants, things from different patient advocacy organizations that can help with that as well.

- So this is a general schematic of how we may think about treating newly diagnosed AML in 2025. So I mentioned we want to think about patient characteristics, think about goals. We want to make sure we're having comprehensive genomic profiling with looking at mutation cytogenetics, then we do our best job we can, which I will say could be better, but trying to determine if patients are fit versus unfit for chemotherapy. And then we look at what are our options. [I'm sorry, my light in my office keeps turning off so I, I'm trying to get it to turn back on. Okay, there we go.]

- So for patients who are fit for intensive chemotherapy, we think about are there additional things we should add on to that treatment based off of different mutations cytogenetics? So core binding factor we add on different additional agent immunotherapy called gemtuzumab, which I'll talk about further. For patients with FLT3 ITD or TKD mutations we add on a FLT3 inhibitor. For patients with secondary AML, which is our therapy related AML, which is AML that can come from prior exposure to chemotherapy or radiation or from another bone marrow disorder or can be defined by certain mutations, we think about using a liposomal form of the cytarabine and daunorubicin called CPX 351 in those situations. And then for patients who are not fit for intensive chemotherapy, as mentioned, the traditional treatment for most patients is hypomethylating agents plus Venetoclax. If patients have an IDH mutation, we may think about an IDH inhibitor plus hypomethylating agents. There are other alternatives that are FDA approved- low-dose cytarabine plus a hedgehog inhibitor called glasdegib, low-dose cytarabine plus venetoclax, gemtuzumab is approved as a single agent or hypomethylating agents, but I will say that the responses are not considered as good as hypomethylating agents with venetoclax. So those are used only in select circumstances.

- And so just adding on here, these are a lot of the research questions that are ongoing right now for acute myeloid leukemia. And that's just thinking about are there patients who are fit, who may be served better with hypomethylating agents and venetoclax? Which FLT3 inhibitors do we pick as there are choices when we add those onto treatment? Could we add venetoclax onto intensive chemotherapy? Other targeted therapies? And then there's also research looking at adding on agents to venetoclax and azacitidine, which I'll talk about as well.

- So for targeted therapies, I'm going to start by talking about FLT3 inhibitors. So FLT3 mutations are present in about a third of patients with newly diagnosed AML. They're both FLT3 ITD, which is internal tandem duplication mutations and then FLT3 tyrosine kinase domain mutations. And so different FLT3 inhibitors may not affect both of those, which I'll talk about. But when those mutations are present, that leads to increased signaling from the FLT3 receptor, which is on the surface of cells and tells these pathways to tell the leukemia cells to grow, proliferate, survive. And so we use these FLT3 inhibitors to block the signaling to help treatment work better.

- And so the three FLT3 inhibitors that are currently FDA approved, the one that's been around the longest is Midostaurin. It targets both the ITD and TKD mutation and it's FDA approved, given in combination with intensive induction and consolidation therapy. Quizartinib is a newer second generation FLT3 inhibitor that just targets ITD mutations and is also approved in that frontline setting in combination with intensive induction consolidation. But it also has an approval of maintenance therapy for patients who are not able to go on to allogeneic transplant. And so Midostaurin does not have that approval because it didn't show benefit in the clinical trials that led to the approval. So that may be something that is factored into your treatment course. And then Gilteritinib is also a second generation FLT3 inhibitor. It targets both ITD and TKD mutations and just currently approved as monotherapy in relapse/refractory AML in that setting.

- So one area of study is as I mentioned, adding on Gilteritinib to Azacitidine and Venetoclax. And so this is a study that's been ongoing, it was led by MD Anderson looking at this triplet therapy is what we call this for patients with either relapse/refractory FLT3 mutated AML and other diseases or newly diagnosed FLT3 mutated AML for patients who are not fit for intensive chemotherapy. And as you can see here, this is kind of the schedule they looked at. The patients had a day 14 bone marrow biopsy and if that was empty at that time, meaning we didn't see leukemia cells, less than 5% blast, then the gilteritinib and venetoclax would stop during cycle one because it can cause myelosuppression, meaning lowering of blood counts, so want to give time for the bone marrow to recover. And for patients who then had recovery of their bone marrow, they went on to receive consolidation therapy with differing doses of the treatment.

- And so this has been in particular very exciting for patients with newly diagnosed AML because we're seeing really high response rates for patients. And so this study was published in 2024 that showed that complete remission rates were 92% with this treatment. And then if you added on complete remission with incomplete count recovery, it was around 96% and patients were having really long what we call relapse-free survival. So living and their leukemia not coming back and then also overall survival. And so due to this excitement, more patients are being treated off label. So you know it's not FDA approved, is what I mean by that. So there was a retrospective study, looking at patients who had been treated with newly diagnosed FLT3 mutated AML who had a FLT3i- containing triplet and again seeing these really high complete remission rates around 82% and high CR + CRi rates with a median overall survival of almost 29 months. And so when you look at patients treated with venetoclax and azacitidine with FLT3 mutations, you can see that, in particular for FLT3 ITD mutations, the complete remission rates are pretty low around 32% though if you add this CRI, it's around 72% and the median overall survival is a little over a year. And so because of this we shouldn't do, you know, cross study comparisons, but there's now an ongoing randomized study trying to determine if this should be our new frontline therapy for patients with FLT3 mutations who are not candidates for intensive induction therapy.

- There's also been a study over the past that was published last year looking at maintenance therapy post-transplant for patients with FLT3 ITD mutations. And this was brought up as one of the questions about what are some research areas looking at that. And so what they found with this study is that they looked at over 300 patients, they were randomized to either gilteritinib or placebo after they had their stem cell transplant. And what they saw is that if they looked at relapse-free survival between the two, if you looked at all patients there, this was not statistically significant, but if you looked at patients who had measurable residual disease, so that means their FLT3 ITD mutation was positive by a PCR test that patients did have improved relapse-free survival with the addition of gilteritinib. And so if that was seen, if patients had positive measurable residual disease before transplant or after transplant. And so now that's becoming really a standard of care of adding on that treatment for patients in that setting. For patients who are not a measurable residual disease positive, there are some questions now of do these, do patients like this truly need a transplant? Can they do well without that? And so that's something that's also being looked at and explored.

- So now moving on to targeted therapies with IDH inhibitors. So IDH mutations, isocitric dehydrogenase as an enzyme that's in your citric acid cycle and cells and tells them to grow and survive. And so what happens is these IDH1 or IDH2 which are in the cytoplasm of the cell or in the mitochondria, respectively, are mutated. And then that leads to making this abnormal what we call onco metabolite or abnormal protein that's called 2-hydroxyglutarate and causes these abnormal cells to grow. And IDH mutations for IDH1 is seen in about 10% of patients, IDH2 in about 20% of patients.

- And so for patients with IDH1 mutations, there are two IDH1 inhibitors that are currently FDA approved. So IVOSIDENIB is one that is approved for newly diagnosed patients given as a single agent. And that's for patients who we really think cannot tolerate any form of chemotherapy including hypomethylating agents. It's also approved in combination with azacitidine. And I'll say most people in looking at the data think this may be a better approach than Azacitidine and Venetoclax though that's not been studied head to head yet. And then also is approved with for relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome as a single agent. Olutasidenib is also approved for patients with IDH1 mutations but in the relapse/refractory setting as a single agent. And then there's one IDH2 inhibitor enasidenib that's approved in the relapse/refractory setting as well.

- And so again, people are very excited about these triplet regimens and so there have been different studies looking at adding either ivosidenib or enasidenib to Azacitidine and Venetoclax for patients who are not intensive induction candidates and the outcomes have been promising thus far. This is a pooled analysis that essentially took a few different studies and put them together to look at outcomes. And if you look at all patients, which there were 60, you can see the two year overall survival with this triplet regimen was around 70% and overall response rates were around 57%. And if you, oh I'm sorry, 95%, if you look at individual mutations with IDH1 and IDH2, you can see the response rates are very high and again these outcomes look better than what we would expect with Venetoclax/Azacitidine alone. So they're ongoing studies looking at these triplet regimens to see again if this will be the new standard of care for patients with IDH mutations.

- Then the newest kid to the block are menin inhibitors. So everyone's very excited about these. So essentially menin is a scaffold protein. It's encoded by this MEN1 gene and it causes when there's NPM1 mutations or something called KMT2A rearrangements. So those are cytogenetic changes, abnormal cells to grow and proliferate and don't differentiate until normal healthy blood cells. And so you can see here the MENIN interacts with this MLL or KMT2A protein and essentially SNDX is also known as revumenib that turns off that interaction and causes leukemia cells to die and cells to differentiate into normal cells. There are lots of menin inhibitors in clinical development right now. Revumenib is the only one that's FDA approved and that's for patients with relapsed/ refractory acute leukemia. So that includes AML and ALL with the KMT2A translocations for both adults and pediatric patients who are a year or older. This is also being reviewed by the FDA for patients with NPM1 mutations. And then ziftomenib is also looking being reviewed by the FDA for patients with relapsed/refractory AML with NPM1 mutations. So there are other menin inhibitors as listed here that are in clinical trials. They do look like they may have different side effect profiles. So we'll see kind of where these land as more become studied and approved as to what may be best options for patients.

- And this is just showing the response rates in patients with KMT2A rearranged AML. So this was the study that led to this AUGMENT-101 and you can see overall response rates were about 63%. CR+CRh rates were around 22%. But CRCR composite complete remission rates were around 42%. And so though the duration of response for patients who did respond to treatment was only around six months, this did allow about a third of patients who are on the study to be able to get to allogeneic transplant.

- This also is what's been published recently as of this past month for patients with NPM1 mutations. And you can see this is similar with an overall response rate of around 47% CR+CRh rate of around 23% also had duration of response for around four to five months. And so again, these are temporizing therapies in this setting but may be able to help patients get to more curative intent treatments such as transplant.

- I think what people are very excited about is looking at these combination treatments. Menin inhibitors are being explored with intensive induction therapy also with Azacitidine and Venetoclax. This is a study that was recently published this past month as well looking at Revumenib in combination with Azacitidine and Venetoclax. And patients could receive up to three cycles of induction if needed and if they had a marrow remission would continue on treatment unless they were able to go on to transplant or disease relapsed or had some type of toxicity. And so if you looked at all patients, which this is this last column here, there there are 43 that have been treated thus far, the complete remission rate has been around 67%. Overall response rates have been around 88%. And I think you know NPM1, patients with NPM1 mutations traditionally do well with venetoclax azacitidine. And so we'll see if that treatment, the addition remains beneficial for that population. As there's a randomized study, randomized studies that are ongoing are about to start looking at that question. But I think what people are very excited about are these responses for KMT2A rearrangements for these types, subtypes of AML. There are only nine patients treated but all patients responded to this treatment and patients who have KMT2A rearrangements don't traditionally respond well traditional chemotherapy or Azacitidine Venetoclax alone. So we're really hopeful this will be a game changer for that population.

- And so in interest of time, I'm going to just move on, but these were some overall survival that was seen for patients, which the median for patients with KMT2A rearrangements was, has been about 18 months but has not been reached for some patients or some patients who are doing better than that. And then for patients with NPM1 mutations around 15.5 months for those treated.

- There are many other targeted therapies and clinical trials right now. And so I just mentioned DH DHODH inhibitors, we're excited to look at for patients with TP53 mutations. There are different RAS inhibitors being looked at for patients with NRAS KRAS mutations, CLK inhibitors, IRAK4 four inhibitors are being looked at. Things like spliceosome mutations which are SF3B1, SRSF2 and others. And so a lot of exciting things going on with treatment that we hope will improve therapeutic options for patients with other subtypes of acute myeloid leukemia.

- Now for cellular therapies and immunotherapies, I just brought up this slide again to show what we're really trying to do is manipulate the immune system to target the acute myeloid leukemia cells. And so when you have, when you undergo transplant, you're really trying to replace the entire immune system. So you get stem cells from a donor that hopefully will make good healthy immune cells, natural killer cells, T lymphocytes, et cetera, that if leukemia tries to relapse it will try to, you know, recognize that as being abnormal and prevent that from happening.

- So for immunotherapy in AML there are monoclonal antibodies that are being looked at. Antibody drug conjugates which use monoclonal, use these antibodies to deliver cytotoxic drugs, bispecific antibodies that target both AML cells and then also connect to immune effector cells like T cells, natural killer cells to try to bring the immune system to the AML cells to help kill these cells and recognize them as abnormal. And there's also different cellular therapies where you take out immune cells from either a patient or a donor, manipulate them in the lab and try to get them to target markers such as shown here on this figure to target the leukemia cells. And then again the immune system works to try to kill those cells.

- Now, right now in acute myeloid leukemia there are a lot of cellular therapies that are being explored in clinical trials. The only immunotherapy that is currently FDA approved besides thinking about allogeneic stem cell transplant is gemtuzumab ozogamicin. And so essentially what this does, it's an antibody drug conjugate that targets the CD 33 that is expressed on the majority of acute myeloid leukemia cells. I'd say about 85 to 90% and it's connected to this calicheamicin drug. And so when it's infused it goes into the cell, it's internalized by the lysosome, breaks apart the drug and then this calicheamicin goes and targets the DNA and the cells and causes the cells to die. Now this is FDA approved in relapse/refractory AML also as a single agent and newly diagnosed AML. I will say that it doesn't have great response rates in those settings. So most of us really limit its use to using in combination with intensive chemotherapy for patients with favorable risk AML as it's been shown to improve overall survival in those settings. In particular for core binding factor AML.

- Now these are other antibodies. So these monospecific antibodies that act like antibodies that your normal white blood cells produce to target like bacteria but they're manmade are being explored. There's a new anti-CD 33 drug called lintuzumab. Nivolumab is an anti-PD1 drug which is FDA approved in other solid tumors. And some bispecific antibodies that have shown good outcomes. Flotetuzumab for one, that targets CD123 on the surface of cells and target CD3 on T cells to bring those to the acute myeloid leukemia cells and are being explored further in frontline settings. And there are also other conjugates where you have cytotoxic drugs like I mentioned with gemtuzumab, these radioisotopes that are connected to these antibody therapies that are being explored. And then this diphtheria toxin that can connect to leukemia cells and potentially kill those and is actually FDA approved in a something called blastic plasmacytic dendritic-cell neoplasm, which is a cousin of acute myeloid leukemia. So that's also being assessed in studies.

- Now many people are excited about chimeric antigen receptor or CAR T-cell therapy. This has been proven to be beneficial for patients with acute lymphocytic leukemia, multiple myeloma, lymphoma, CLL but unfortunately it's been more difficult to develop in acute myeloid leukemia. And so how this treatment works is patients undergo collection of their blood or potentially donors and the T cells are collected in the lab. Those T cells are manipulated and reprogrammed to target different receptors on the surface of the acute myeloid leukemia cells as shown here. Those are allowed to grow and divide and to make more of these T cells and then are infused back into the patient to hopefully attack cancer cells. And so as you can see here, there are lots of different targets that are being explored. These are different targets that are being looked at in the lab and other models to see if they could be used for patients. And so we're very hopeful that we're becoming closer to you know, having an effective CAR T-cell therapy for acute myeloid leukemia.

- People are also looking at natural killer cells. So these are essentially a type of lymphocyte that has a role in the immune system. It can release things like these different granzymes perforin, interferon gamma, TNF alpha that, when they connect to cancer cells, helps kill these cells. And so the neat thing about these natural killer cells is they can be, you can obtain them from different sources so they can be from different healthy volunteers, umbilical cord blood from healthy babies who their parents have donated their umbilical cords, manipulated in the lab or grown in the lab and essentially can be manipulated to be activated to target different also markers within the cancer cells and hopefully will lead to responses for patients. But this is also something that is still under clinical study and we're waiting to see if there's an effective natural killer cell for this as well.

- And then I was going to mention because it was brought up in a question, dendritic cells. So these are specialized immune cells that present antigens to other immune cells like T cells to help them recognize cells as abnormal and fight against cancer cells. And so those are being explored in particular as vaccine studies and so those are taken out of patients and then also exposed to an antigen allowed to grow and then essentially given as a vaccination to patients. And so we'll see if those are effective for patients as well.

- And so lastly I was going to just mention acute promyelocytic leukemia because I believe there are some questions about that. So that's the special subtype of acute myeloid leukemia. It's characterized by the specific translocation- so chromosome change between chromosome 15 and 17 and it's about 10% of all acute myeloid leukemia cases. So it is defined as either low risk disease where white blood cell count is less or equal to 10,000 on presentation or high risk when the white blood cell count is greater than 10,000. And so therapy for APL has really changed, especially for low risk disease with the introduction of arsenic and then high dose vitamin A or ATRA. And so for patients, if they can get through some of the initial potential complications of therapy, the majority, vast majority are cured with this therapy. It's very unusual to see relapse with that. And then for patients with high risk disease, still very potential curative disease but requires more intensive chemotherapy along with ATRA and sometimes we give gemtuzumab in the setting as well. So patients can present with bleeding and thrombotic complications. So blood clots and so there can be risk of dying from these complications during initial treatment. So patients are kept in the hospital during that time to really closely monitor for that and help give transfusion support to try to prevent these complications. But the biggest area of research for this is really looking to see if, instead of giving arsenic by IV if this maybe can be formulated to give by pill. And that's especially important when you start getting to consolidation. So when patients get out of the hospital and giving arsenic consolidation right now that's essentially a month on a treatment, a month off, a month on a treatment and a month off. And so people will come Monday through Friday for four days a week to get these IV infusions and it's for about off and on for eight months of treatment. And so it would be really great if we had an oral version of this so patients didn't have to come to the clinic as much to continue with their treatment once they're in remission.

- And so with that I just wanted to end in stating kind of two things. So even though we've had all of this improvement new therapeutics, we still are not curing the vast majority of patients with acute myeloid leukemia. And so that's why it's very important to continue with clinical trials, new therapies to try to do a better job also to try to have decreased side effects from our treatments as well. And then the other thing is that we want to try to make sure that patients are actually being treated with their disease. And so this was a study that was presented back in 2023 at one of our big hematology meetings, essentially looked at real world data, over 5,000 patients with newly diagnosed AML and about 900 with relapse/refractory AML. And you can see here more patients are being treated with azacitidine or hypermethylating agents and venetoclax based regimens as depicted in this kind of high or darker blue. But still a third of patients or more are not being treated with, are being treated with any therapy. And that may be appropriate for some patients based off of their preference or decision, but we just want to make sure that patients are aware of different options and that there are treatments that are available for people who are, even if they're not candidates for intensive chemotherapy.

- And so with that I just want to say thank you for the opportunity to speak with y'all today on this and happy to answer any questions.

- Wonderful, thank you so much. I think that was very helpful. And the one thing that I think it was great that you stated upfront is that so much of treatment nowadays is really focused on the biomarkers. And so for anyone who is on this call right now who isn't familiar with that, you know sort of what your or your loved one's biomarkers are and how that is kind of influencing their treatment, it's really a good place to start at your next visit with the doctor to make sure that you understand, you know, like what are the biomarkers that are being seen in the tests that are being run for the patient. And Dr. Mims that I'm sure you mentioned a couple of those tests but maybe might be helpful just to mention again what are the tests where, if the patients or caregivers go back into the electronic health records, they can probably see that information.

- Sure, so those are typically listed as cytogenetics or chromosome analysis for looking initially at how the DNA is wound and then for the specific gene mutations, those typically are listed as myeloid mutational panel. Sometimes they can be listed as FLT3 or IDH PCR testing, but sometimes they're referred to also as next generation sequencing. And so those really are standard for all patients with newly diagnosed AML. And then also again for patients who relapse, as I mentioned as those can change. And so it's really important to know those 'cause those can, those affect how we should approach treatment and also may offer you more options to know those.

- Great, thank you. And just as a little bit of a reminder for patients and caregivers, we have a lot of that information on our website and I can share the link to that, that page on our website in the chat in a few minutes. But you can find a lot of information about the different types of tests and what they tell us on our website. And also we just had a webinar about a couple about a month ago that was focused specifically on FLT3 treatments and also another webinar that was more broadly on genetics and biomarkers in leukemia. So please visit our website for the videos from those other webinars. So let's just get to some of these questions real quick. One person asked will FLT3 lead to poor outcome? I guess maybe the question is, if it's untreated, but you mentioned there are many treatments possible for FLT3 mutations in AML now.

- Yep. And then I would also just add the FLT3 TKD mutations are, do not seem to have as effects on outcomes as the FLT3 ITD mutations. And then you know, as mentioned, there are a lot of things looking at measurable residual disease and seeing do all patients with FLT3 ITD mutations truly need a transplant for cure or not? And then we'll see with addition of triplet therapies and non-intensive induction therapies, if that may also, you know, be cured or help people have longer survivals.

- Great. And then also, what percentage of teenagers get AML? Do you have a rough estimate of that? I mean,

- So it's, it's definitely you know, the average age for acute myeloid leukemia is around 66 and so there's kind of a bell curve where it can affect unfortunately infants and then becomes higher as as you get older. So I would say that's not common to see in what we call adolescent and young adults, but I can't say the exact percentage.

- And it's generally speaking though, AML is less common than ALL in Correct, yeah, adolescence. So okay, just turning to some of the questions that were submitted through the registration, let's see. If someone were to make a list of potential advancements, it could be quite long. Unfortunately the timeframe for any of those to come to fruition would also be quite long. What advancements do you think might be practically useful soon?

- Okay, sure. So I think what we're hoping is that, you know, the addition of some of these targeted therapies to our standard treatments and even adding venetoclax to intensive chemotherapy may be helpful. Those are not necessarily things you have to wait to be on a clinical trial, though it does help us answer questions for other patients if we do study those on clinical trials. But some people are going ahead and using those off-label just because they seem to be much better than what our expectations are with standard treatments.

- Okay. And you mentioned clinical trials. So one person asked how would we go about finding clinical trials for issues that are unclear or emerging? So this person specifically highlighted MPNs with different genetics. I mean, do you have a suggestion generally for clinical trials? We have a tool for clinical trial matching on our website, but I'm interested to hear what your thoughts are.

- Sure. So, you know, it can be a little bit difficult, I would say, you know, you can look up things on clinicaltrials.gov, but I don't know that it's as patient friendly as it should be. There are some other patient advocacy groups as well that I know have clinical trial navigators who can help you do that, like the Leukemia & Lymphoma Society, as you mentioned, your website. And so those would be good resources that I would recommend.

- Great. Okay. Unfortunately we're not going to be able to get to everybody's questions. What is the success this one says, what is the success rate for Dacogen?

- Oh Dacogen and Venetoclax. Right, for relapsed AML post-transplant. So I think that's a little bit nuanced just because it can depend on what leukemia is treated with initially, kind of what are the different cytogenetics mutational features. It can be successful for patients in that setting, but it really just depends on the individual patients leukemia to discuss that and, and not generalities.

- Yeah. Okay, great. I think unfortunately we're going to need to start to wrap things up because we do have another webinar immediately following this one. So I'm going to bring up those slides one more time and I just wanted to mention that there are some great resources on our website. There's also- I think you should be able to see my screen now- there's the NCCN patient guidelines, which I'm not sure if everyone is familiar with, but that's a very good place to go for, you know, kind of a nice kind of very covers a lot of ground in a very succinct way in patient terms that hopefully patients are available or making them, sorry, I can't seem to talk right now. Making use of those, if you're not familiar with them, please do visit the website here, nccn.org/patients/guidelines Dr. Mims, any other closing thoughts?

- Yeah, I was just going to say, you know, I think again, you know, it's important to have good conversations, feel comfortable with your physician, you know, it's always okay to reach out and ask for a second opinion, make sure you're comfortable with the plan and again, just be your own best advocate and, and people shouldn't get mad or be upset with you about that.

- Yeah, great, great advice. Thank you so much for that. I appreciate you mentioning that, this whole concept of shared decision making and really working with your care team to make sure that what they're proposing is going to work for you because nowadays there are other options in many cases, so it's good to, to explore the options and make sure that whatever you're kind of going to go through works for you and your family or your caregivers or whatever. So, great. Well thank you so much again, I think this was very helpful. Once again, thanks to our sponsors and thanks for everyone's participation and hopefully we will see some of you on our next webinar about ALL and if not, please, you know, stay in touch with Leukemia Research Foundation and visit us and keep in touch. So thank you so much Dr. Mims, have a great night and we'll be posting the video shortly and also, you know, we'll send that survey out that I mentioned earlier about just to get some feedback on the program. So thanks everyone. Have a great night.